AIDS, the acquired immunodeficiency syndrome caused by the HIV-1, the human immunodeficiency virus, is a life-threatening disease spreading around the globe with alarming speed. By the year two thousand it is estimated 40 million people will be infected with HIV. The immunosuppression resulting from HIV infection causes loss of resistance to opportunistic infections in AIDS patients, P. carinii caused pneumonia being the major cause of deaths. The development of vaccines, ideal to combat an infectious disease have not yet resulted in a vaccine that would be effective not only against the laboratory strains but more importantly against the primary strains of HIV. This problem is further aggravated by the hypermutating nature of HIV. Gene therapy, another promising approach is also yet to bear fruit. In the absence of an effective vaccine and clinically successful gene therapies, other approaches must be sought to prevent further spreading of the HIV infection, to circumvent the effect of the virus in already infected individuals, and to prevent and treat the opportunistic diseases associated with AIDS. We propose a bioorganic approach to combat HIV infection, AIDS and PCP associated with it. This will consist of the development of agents that by interaction with macromolecules vital to HIV's survival will block their action. We propose to design and synthesize compounds that will block the entry of the virus into host cells by preventing the binding of gp120 to CD4, compounds that by interfering with the replication mechanism of HIV inhibit it's maturation. Novel types of highly versatile macrocyclic compounds, developed by us in the first phase of the project, are of vital importance in these blocking events. These will be synthesized by the novel macrocyclization reaction we developed during the ongoing project. The first generation of macrocycles, and new macrocycles designed on the basis of leads obtained in cytotoxicity/cytopathicity tests, as well as their metal complexes and conjugates will be targeted against HIV. The macrocycles will be derivatized with spacer-arms, or they will be introduced during the syntheses. Spacer-arms both hydrophilic and hydrophobic will be employed. Metal chelates of amide, imine and polyaza macrocycles will be used to effect oxidative cleavage of protein or nucleic acids components of HIV. These macrocyclic cleavers will be covalently connected to the carriers, such as antibodies and antisense oligonucleotides, so as to effect cleave in a site and sequence specific manner.